Liver fibrosis is a gradual process of increased production and decreased degradation of extracellular matrix materials. It is generally viewed that damage to hepatic cells initiates the process of fibrosis formation through activation and secretion of multiple cellular factors from Kupffer cells (macrophages which line the liver sinusoids). Such factors, in addition to factors secreted by damaged hepatocytes, thrombocytes, and endothelial cells of the hepatic sinusoid and other mediators, activate hepatic stellate cells. Activated hepatic stellate cells differentiate into myofibroblasts, which proliferate and synthesize a massive amount of extracellular materials that gradually accumulate, resulting in the development of liver fibrosis.
Liver fibrosis is common to liver diseases of many etiologies, including chronic viral hepatitis B and C, autoimmune liver disease, such as autoimmune hepatitis and primary biliary cirrhosis, alcoholic liver disease, nonalcoholic fatty liver disease, metabolic disorders, such as lipid, glycogen, or metal storage disorders, and drug-induced liver disease. The fibrosis exhibited in these disorders results from chronic insults to the liver from, for example, viral infection, alcohol, or drugs.
Hepatitis C, for example, is one of the leading causes of chronic liver disease in the United States, where an estimated 3.9 million people are chronically infected with hepatitis C virus (HCV) and approximately 30,000 new cases of acute HCV occur each year. Thus, the prevalence of hepatitis C is estimated to be 1.8% in the United States, with as many as 10,000 deaths per year resulting from chronic HCV infection (Alter, Semin. Liver Dis. 15:5-14 (1995)). World-wide, the prevalence of chronic HCV infection is estimated to be about 3% (J Viral Hepat 6:35-47 (1999)). Moreover, death, hospitalization and liver transplantation as a result of chronic hepatitis C have increased significantly in the past decade (Hepatology 36:S30-42 (2002)). Liver fibrosis is the main determinant of hepatitis C virus related morbidity and mortality (Lancet 349:825-323 (1997)). Furthermore, the stage of fibrosis is prognostic and provides information on the likelihood of disease progression and response to treatment (Hepatology 36:S47-564, 5 (2002); N Engl J Med 347:975-82 (2002)). The presence of significant fibrosis (equivalent to METAVIR F2 or greater) as determined by liver biopsy, is widely accepted as an indication to commence treatment (Gut 49:11-21 (2001); J Hepatol 31:3-8 (1999); Hepatology 39:1147-71 (2004)). The presence of cirrhosis has implications regarding screening for hepatocellular carcinoma and esophageal varices (J Hepatol 31:3-8 (1999)).
Liver biopsy is currently the gold standard for staging fibrosis, but has well documented complications including pain, bleeding and, rarely, death (Gut 36:437-419, (1995); N Engl J Med 344:495-500 (2001)). Liver biopsy is also expensive, as are the costs associated with treating any resulting complications. In addition, inter- and intra-observer error may lead to incorrect staging (Hepatology 36:S47-564, 5 (2002)), as may sampling error in up to 33% of biopsies (Am J Gastroenterol 97:2614-8 (2002)).
Routinely measured serum markers, used either individually or in combination, have been examined as alternatives to liver biopsy for staging fibrosis among hepatitis C patients. Platelet count, ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT), or a combination of AST and platelet count, are reliable predictors of cirrhosis (Arch Intern Med 163:218-24 (2003)). However, their predictive value for mild or moderate fibrosis is insufficient to be of clinical utility (Hepatology 38: 518-26 (2003); Hepatology 39: 1456-7 (2004)). More complex models which include routinely available analytes such as cholesterol, γ-glutamyltransferase (GGT), platelet count, and prothrombin time, have a high negative predictive value (NPV) for excluding significant hepatic fibrosis, but have poor positive predictive value (PPV) and are only applicable to approximately one third of patients (Hepatology 39:1456-7 (2004)). A recently reported model incorporating measures of insulin resistance and past alcohol intake, reliably predicted significant fibrosis, but was less accurate in excluding significant fibrosis (Hepatology 39:1239-47 (2004)).
In efforts to improve the accuracy of noninvasive methods of staging liver fibrosis, several non-routinely-available biochemical markers associated with collagen and extra-cellular matrix deposition/degradation have been examined. Serum levels of hyaluronic acid, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and matrix metalloproteinase-2 (MMP-2) correlate with liver fibrosis, but by themselves have low predictive value for diagnosing significant fibrosis (J Gastroenterol Hepatol 15:945-51, 18 (2000); J Hepatol 26:574-83 (1997)). “FibroTest” (BioPredictive S.A.S., Paris, France), which combines multiple biochemical markers with age and gender, was accurate in detecting significant fibrosis in just under half of patients from a center in France (Lancet 357: 1069-75 (2001)). However, when applied to a population of hepatitis C patients from our institution, FibroTest was less accurate and had a PPV of less than 80%. (Clin Chem 49: 450-420 (2003))